Mechanism responsible for 5-(tetradecyloxy)-2-furoic acid inhibition of hepatic lipogenesis.

The compound 5 (tetradecyloxy) 2 furoic acid (TOFA), a hypolipidemic agent, inhibits glycogen and net glucose utilization, lactate and pyruvate accumulation, and fatty acid synthesis by hepatocytes prepared from meal-fed rats. It stimulates the accumulation of glucose, ketogenesis from endogenous substrates, and the oxidation of [1-%]oleate. These effects of TOFA do not appear to be a consequence of inhibition of the mitochondrial citrate transport system. Uncoupling of mitochondrial respiration would occur at concentrations of TOFA which inhibit citrate efflux. ATP levels are not lowered by TOFA. Furthermore, as determined by the digitonin fractionation method, TOFA increases citrate in both the cytosol and the mitosol. Hepatocytes incubated with TOFA have reduced levels of CoA and acetyl-CoA but elevated levels of long chain acyl-CoA esters. Isolated microsomes readily form the CoA ester of TOFA (TOFyl-CoA), suggesting that the increase in long chain acyl-CoA esters caused by TOFA with intact hepatocytes is due at least in part to the accumulation of TOFyl-CoA. Although not inhibited by TOFA, acetyl-CoA carboxylase is inhibited by TOFylCoA. It is proposed that many of the metabolic effects of TOFA can be explained by TOFyl-CoA inhibition of acetyl-CoA carboxylase. The resulting decrease in malonyl-CoA limits fatty acid synthesis for want of substrate by fatty acid synthetase but stimulates fatty acid oxidation and ketogenesis by relieving the inhibition on carnltine acyltransferase I. Glycolysis is inhibited, perhaps as a consequence of accelerated fatty acid oxidation, causing a decrease in the rate of net glucose and glycogen utilization, a decrease in lactate and pyruvate accumulation, and an increase in glucose release into the incubation medium.